Traditionally, communication between neurons in the cerebral cortex, and, indeed, within much of the brain, is believed to be mediated largely or solely through the rate and pattern of action potentials in a pulse or digital code. Recently, however, we have shown that the average amplitude of synaptic potentials evoked by action potentials is dependent upon the membrane potential of the presynaptic neuron and that these membrane potential changes travel long distances down the axon. This means that information communication between nearby cortical neurons may use a combined pulse and graded or analog and digital code. Here we will examine the mechanisms of this possible analog code. Specifically, we will examine the mechanisms by which the membrane potential of cortical neurons can influence the amplitude of synaptic potentials that the neuron induces in nearby cells. We will perform whole cell recordings from synaptically connected pairs of neurons in prefrontal cortical slices maintained in vitro. In addition, we will examine the possible involvement of changes in presynaptic Calcium concentrations through two-photon imaging of Ca2+ levels in presynaptic boutons while their parent soma is moved to different membrane potentials. Our investigations will also examine the electrophysiological properties of intracortical axons, particularly those properties that may be involved in detecting changes in membrane potential at the soma. We are particularly interested in the properties of voltage-dependent K+ currents within intracortical axons and how these may control axonal excitability. To examine these in detail, we will perform simultaneous whole cell patch clamp recordings from the soma and axon of cortical neurons during the application of voltage clamp steps and examine the respond of the axons to the application of toxins that are specific for different types of K+ channel. Be performing whole cell recordings from intracortical axons in mice in which particular K+ channels have been knocked out, we will be able to examine the involvement of specific ionic channels and subunits in these effects. Through this combination of synaptic and axonal electrophysiological investigations, we will achieve a more detailed and integrated understanding of how information communication operates within the cerebral cortex. This information will allow us to better manage disorders of axonal and synaptic communication including multiple sclerosis and epilepsy. PUBLIC HEALTH RELEVANCE: The proper function of synaptic transmission and axons, the output of neurons, is critical to the proper functioning of the brain, particularly the cerebral cortex. Numerous neurological disorders result from disruption of synaptic and axonal function. Our study will examine important basic properties of synaptic and axonal function in the cerebral cortex.